Adenosine is a nucleoside that occurs naturally in mammals. The heart, for instance, produces and releases adenosine in order to modulate heart rate and coronary vasodilation. Likewise, adenosine is produced in the kidney to modulate essential physiological responses, including glomerular filtration rate (GFR), electrolyte reabsorption, and renin secretion.
Adenosine exerts its biological effects by interacting with a family of adenosine receptors identified as A1, A2a, A2b, and A3, all of which modulate important physiological processes. For example, A2A adenosine receptors modulate coronary vasodilation, A2B receptors have been implicated in mast cell activation, asthma, vasodilation, regulation of cell growth, intestinal function, and modulation of neurosecretion (See Adenosine A2B Receptors as Therapeutic Targets, Drug Dev Res 45:198; Feoktistov et al., Trends Pharmacol Sci 19:148-153), and A3 adenosine receptors modulate cell proliferation processes.
Adenosine elicits a response in the kidney through the adenosine A1-receptor. Activation of the adenosine A1 receptor in the kidney stimulates sodium reabsorption from the tubular lumen, and also constricts the afferent arterioles, providing an increase in renal vascular resistance, which leads to a decrease in GFR. Conversely, blockade of the A1 adenosine receptor decreases afferent arteriole pressure, leading to an increase in GFR and urine flow, and sodium excretion.
Decreases in renal function are frequently seen in patients with congestive heart failure (CHF). This phenomenon has been treated with loop diuretics such as furosemide, but it has been shown that use of such diuretics decreases GFR, which is a very undesirable consequence in patients already compromised with CHF.
Accordingly, it is desired to provide highly selective A1 adenosine receptor antagonists, thus avoiding the side effects associated with the biological effects of interaction with the A2a, A2b, and A3 adenosine receptors. Such compounds would be useful as diuretics that promote sodium excretion, are GFR sparing, and particularly useful in the treatment of CHF.